rs767827357

chr10-110799866-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001134363.3(RBM20):c.1748G>A(p.Gly583Asp) variant causes a missense change. The variant allele was found at a frequency of 0.0000264 in 1,551,984 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G583S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: RBM20 NM_001134363.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: 4.90

Genes affected

RBM20 (HGNC:27424): (RNA binding motif protein 20) This gene encodes a protein that binds RNA and regulates splicing. Mutations in this gene have been associated with familial dilated cardiomyopathy. [provided by RefSeq, Apr 2014]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.18673912).
• BS2: High AC in GnomAdExome at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RBM20	NM_001134363.3	c.1748G>A	p.Gly583Asp	missense_variant	7/14	ENST00000369519.4
RBM20	XM_017016103.3	c.1583G>A	p.Gly528Asp	missense_variant	7/14
RBM20	XM_017016104.3	c.1364G>A	p.Gly455Asp	missense_variant	7/14
RBM20	XM_047425116.1	c.1364G>A	p.Gly455Asp	missense_variant	7/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RBM20	ENST00000369519.4	c.1748G>A	p.Gly583Asp	missense_variant	7/14	1	NM_001134363.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152228 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000379 AC: 6 AN: 158272 Hom.: 0 AF XY: 0.0000479 AC XY: 4 AN XY: 83442

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000121

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000487

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000271 AC: 38 AN: 1399756 Hom.: 0 Cov.: 30 AF XY: 0.0000275 AC XY: 19 AN XY: 690364

Gnomad4 AFR exome AF: 0.0000316

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000269

Gnomad4 OTH exome AF: 0.0000516

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152228 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74376

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000761 Hom.: 0

Bravo AF: 0.0000151

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Apr 25, 2017	Found in a 16 year-old male with lone atrial fibrillation and a family history of heart failure and arrhythmias. Testing was done at Invitae. p.Gly583Asp (c.1748G>A) in exon 7 of the RBM20 gene (NM_001134363.2) Chromosome position: 10:112559624 G / A The RBM20 gene is associated with autosomal dominant dilated cardiomyopathy (DCM) (MedGen UID: 416441). Based on the information reviewed below, including that Aspartic Acid is accepted as the default amino acid at this codon in at least 21 species, we classify this as a Variant of Uncertain Significance, Probably Benign, concluding that there is not sufficient evidence for its pathogenicity to warrant using it for predictive genetic testing. This variant has not previously been reported in the literature in association with disease. This is a nonconservative amino acid change, resulting in the replacement of a nonpolar Glycine with a negatively-charged Aspartic Acid. Glycine at this location is poorly conserved across ~100 vertebrate species for which we have data, and Aspartic Acid is in fact the default amino acid in at least 21 species. According to the Invitae report, algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). There is no Likely Pathogenic or Pathogenic missense variant currently listed in ClinVar at a nearby residue (+/- 10), which may indicate that this part of the protein is tolerant of change. This variant was reported in 8 individuals in the gnomAD database, which includes ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. However, there are variant calls at this site for only 91,833 individuals, indicating that it may be a low-quality site. Specifically, the variant was observed in 3 Latino individuals (for the highest allele frequency: 0.012%), and 5 non-Finnish Europeans. Out patient’s ancestry is Latino. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. The curators made an effort to exclude individuals with severe pediatric diseases. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 16, 2023	Identified in a teenager with early onset atrial fibrillation who harbors multiple cardiogenetic variants (Goodyer et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31638414) -

Dilated cardiomyopathy 1DD Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Oct 27, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Apr 24, 2018

- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 12, 2021

The p.G583D variant (also known as c.1748G>A), located in coding exon 7 of the RBM20 gene, results from a G to A substitution at nucleotide position 1748. The glycine at codon 583 is replaced by aspartic acid, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species, and aspartic acid is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.22
Cadd	Benign	21
Dann	Uncertain	0.99
Eigen	Benign	0.082
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.85	D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.58	T
MutationTaster	Benign	0.99	D
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.40
Sift	Benign	0.44	T
Sift4G	Benign	1.0	T
Vest4		0.28
MVP		0.58
ClinPred		0.26	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs767827357; hg19: chr10-112559624;